Artificial sweeteners (also called non-nutritive sweeteners, NNS) are 100-20,000 times sweeter than sucrose and provide sweet taste with no or minimal contribution to caloric intake. Consumption of NNS has steadily increased in both children and adults in the US. This trend will likely continue, since sugar intake has been linked to the development of obesity, and NNS offer a palatable alternative. However, several large cross-sectional studies have suggested adverse metabolic effects of NNS resulting in similar consequences as high sugar intake, including weight gain, insulin resistance, fatty liver disease, diabetes and cardiovascular disease. In a previous pilot study, we observed that diet soda (Diet Rite Cola) augments glucose-stimulated GLP-1 secretion in young, healthy volunteers. Subjects 12 to 25 years of age participated in two 75 gram oral glucose tolerance tests (OGTT) on separate days. Ten minutes prior to the glucose load, subjects drank 240 mL of either caffeine-free diet soda (Diet Rite cola) sweetened with sucralose and acesulfame-potassium, or unflavored carbonated water, in randomized order, with each subject serving as his/her own control. In the presently ongoing study, we have shown that the NNS sucralose and acesulfame-potassium in diet soda are partially responsible for the observed increase in GLP-1, but that the taste of diet soda or other ingredients also play a role. Furthermore we found that insulin secretion is slightly higher when study participants receive NNS (either in water or in diet soda) immediately before an OGTT compared to water as a pretreatment. We speculate that this may be due to pancreatic beta cell sweet taste receptor activation. We are also studying the effects of NNS in individuals who have undergone bariatric surgery (Roux-en-Y) since these persons have very high incretin concentrations, which may be important for their weight loss and lack of weight regain. It is unknown whether NNS can further induce GLP-1 responses. Additionally, we are testing the effects of the sweet taste receptor inhibitor lactisole on GLP-1 secretion. In collaboration with the University of Oklahoma, we are quantifying NNS concentrations in breast milk after a known exposure (diet soda) of the mother and repeated breast milk sampling for 6 hours. In another collaboration with the University of Chicago, we are investigating whether NNS plasma concentrations can explain the varying insulin secretory responses observed in the study participants.